Abstract
Patients with steroid-resistant nephrotic syndrome (SRNS) who develop resistance to immunosuppressive agents, defined as refractory SRNS, have poor renal outcomes. Although the chimeric anti-CD20 monoclonal antibody rituximab has shown efficacy for frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome, its efficacy for refractory SRNS remains uncertain due to limited data. According to previous case reports, 50.4% of patients with refractory SRNS showed clinical improvements after rituximab treatment. Remission rates in patients with initial steroid resistance and late steroid resistance were 43.9 and 57.7%, respectively, and 41.5 and 63.6% in patients with focal segmental glomerulosclerosis and minor glomerular abnormalities, respectively. However, various factors (race, disease severity, number of rituximab doses, concomitant treatments, and observation period) differed among these observational studies and their consensus may also have been affected by potential publication bias. Rituximab monotherapy may have some degree of efficacy and lead to satisfactory outcomes in a subset of patients with refractory SRNS. However, administration of concomitant treatments during rituximab-mediated B cell depletion, such as methylprednisolone pulse therapy, daily oral prednisolone therapy, and immunosuppressive agents, may lead to better outcomes in these patients. Large-scale, multi-center prospective studies are needed to evaluate the efficacy and safety of such regimens.
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Introduction
Idiopathic nephrotic syndrome is the most common glomerular disease in children and is characterized by hypoalbuminemia and edema caused by heavy proteinuria. A recent nationwide analysis in Japan revealed an incidence rate of 6.5 cases per 100,000 children per year, with half of cases diagnosed in children younger than 5 years of age [1]. Idiopathic nephrotic syndrome occurs less frequently in Caucasian populations (two cases per 100,000 children per year). Almost 10% of cases develop steroid-resistant nephrotic syndrome (SRNS). Renal prognoses for children with SRNS are poor, and 10-year renal survival was reported at approximately 60% [2, 3]. Renal outcomes in patients who develop resistance to both steroids and immunosuppressive agents, defined as refractory SRNS, are especially poor. A cohort study of 1354 SRNS patients enrolled in the PodoNet Registry in Europe showed that 10-year end-stage renal disease (ESRD)-free survival rates were 94%, 72%, and 43% in children with complete remission, partial remission, and no remission, respectively [3]. Thus, achieving remission is crucial for optimal long-term renal prognosis.
The standard induction therapy for children with SRNS is a calcineurin inhibitor or combination treatment with calcineurin inhibitor and methyl prednisone pulse therapy (MPT) [4]. Several case series have reported the efficacy of MPT, renin-angiotensin system inhibitors, plasma exchange, and low-density lipoprotein in reducing proteinuria in children with SRNS, although few randomized controlled trials (RCTs) have been conducted [5,6,7,8,9,10,11,12]. Hamasaki et al. reported high remission rates in patients with minor glomerular abnormalities (MGAs) treated with a regimen of cyclosporine (CsA) and oral prednisolone (82.1%) and in patients with focal segmental glomerulosclerosis (FSGS) treated with a CsA, MPT, and oral prednisolone regimen (85.7%). A Cochrane review [4], the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [13], and the 2013 Japanese guideline for pediatric idiopathic nephrotic syndrome [14] all designated calcineurin inhibitors as the first-line induction therapy for patients with SRNS. However, 20–30% of children with SRNS fail to achieve remission after first-line therapies, a condition defined as refractory SRNS. Standard treatment regimens for patients with refractory SRNS have not yet been established.
Rituximab is a chimeric anti-CD20 monoclonal antibody which depletes B-cells. Its ability to prevent or delay relapse in patients with frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome (FRNS/SDNS) has been demonstrated in several case series and RCTs [15, 16]. Rituximab was approved in Japan by the Ministry of Health, Labor, and Welfare for complicated FRNS/SDNS on August 29, 2014, based on the results of a multicenter, double-blind, placebo-controlled RCT [15, 16]. However, the efficacy of rituximab therapy for refractory SRNS remains uncertain and is based on limited reports, most of them observational studies. The aim of rituximab administration differs by clinical condition: the goal is to prevent relapse in patients with FRNS/SDNS and to induce remission in patients with refractory SRNS. In this review, we highlight recent studies of rituximab treatment for refractory SRNS in children, attempt to retrospectively assess its efficacy, and discuss future perspectives.
Case studies and case series of rituximab therapy for refractory SRNS
Supplementary Tables 1 and 2 show case reports [17,18,19,20,21,22,23,24,25,26,27,28,29] and case series [30,31,32,33,34,35,36,37,38] of rituximab therapy for children with refractory SRNS. Bagga et al. described excellent outcomes in five children (aged 2.8–16.0 years) receiving rituximab as a single weekly infusion of 375 mg/m2 for 4 weeks (four complete remissions and one partial remission) [30]. This was the first report of rituximab as induction therapy in pediatric or adult patients with refractory SRNS. Subsequently, reports of positive outcomes following rituximab therapy for refractory SRNS continued to be published [17,18,19,20].
However, negative outcomes have also been reported following rituximab therapy, such as a case report showing no response to rituximab in refractory SRNS [21, 27, 31, 36]. Gulati et al. treated 33 patients with refractory SRNS (including three adult cases) with four doses of rituximab [31]. Nine patients (27.2%) achieved complete remission, 7 patients (21.2%) achieved partial remission, and 17 patients (51.5%) showed no response following rituximab therapy. The same group also published a similar result in 2015 [36]. Since the consensus of these case reports and case series was that the efficacy of rituximab for refractory SRNS, per se, might be unsatisfactory, concomitant treatments following rituximab administration have been considered.
We published a case series describing 10 patients with refractory SRNS treated with a combination of rituximab, MPT, and immunosuppressive agents [35]. Seven patients (70%) achieved complete remission, one patient (10%) achieved partial remission, and two patients (20%) showed no response. The two patients showing no response to treatment progressed to ESRD. Nakagawa et al. also reported excellent results using a similar protocol [28]. By contrast, Fujinaga and colleagues and Hirano et al. described three cases with refractory SRNS who achieved complete remission after receiving oral daily prednisolone therapy following rituximab therapy [24, 26, 29]. Basu et al. showed that administration of mycophenolate mofetil following rituximab treatment resulted in higher remission rates [37]. Rituximab therapy with additional subsequent treatments, such as MPT, oral daily prednisolone therapy, and immunosuppressive agents, might be more effective in patients with refractory SRNS than rituximab alone. However, one must be aware of potential publication bias among these observational reports. The efficacy and safety of such regimens should be investigated using large prospective studies.
RCTs examining rituximab therapy for refractory SRNS
The only RCT examining rituximab therapy for children with refractory SRNS was published by Magnasco et al. in 2012 (Supplementary Table 3) [39]. Thirty-one children with refractory SRNS were randomized into either the rituximab group (n = 16) or the placebo group (n = 15). All patients were negative for NPHS2 and WT1 mutations. Age, serum albumin levels, daily urinary protein excretion, and renal biopsy results were comparable between both groups. Patients randomized to the rituximab group received two doses of rituximab. After 3 months of treatment, three patients in both groups achieved complete remission. Although proteinuria decreased in patients with delayed resistance, rituximab did not reduce proteinuria in early-resistant patients. This study concluded that addition of rituximab to standard regimens did not improve clinical outcomes for children with refractory SRNS.
However, the observation period of this study was only 3 months, which may be too short to evaluate the efficacy of treatments for refractory SRNS. Moreover, the impact of additional treatments such as MPT following rituximab therapy was not examined in this study. These factors might have served to dilute the effects of rituximab therapy in this study.
Response to rituximab therapy for refractory SRNS according to type of steroid resistance and renal pathology
Table 1 shows remission rates following rituximab therapy in patients with refractory SRNS. One must be aware of possible publication bias, as positive results are more likely to be more reported than negative results, especially in case reports. Among case series, remission rates varied from 18.8 to 80.0%. However, race, disease severity, number of rituximab doses, concomitant treatments after rituximab, and observational period differed among these studies.
Table 2 shows responses to rituximab therapy stratified by type of steroid resistance. In the studies by Gulati et al. [31], Sinha et al. [36], Basu et al. [37], and Magnasco et al. [39], patients with late steroid resistance showed higher remission rates, although other reports did not confirm this finding. The overall remission rates of patients with initial steroid resistance and late steroid resistance were 43.9 and 57.7%, respectively; the difference between these figures was not statistically significant. Although patients with congenital nephrotic syndrome were excluded in these studies, it is possible that some patients with initial steroid resistance might have carried genetic mutations leading to nephrotic syndrome, as the number of established susceptibility genes for nephrotic syndrome has been increasing.
Table 3 shows responses to rituximab therapy according to renal biopsy findings. In the studies by Gulati et al. [31], Sinha et al. [36], Basu et al. [37], patients with FSGS showed lower remission rates than those with MGAs. The overall remission rates were 41.5% for patients with FSGS and 63.6% for those with MGAs; this difference was statistically significant (p = 0.003). However, as pathological findings sometimes change in a single patient, there is a possibility that MGA and FSGS represent pathologically identical clinical entities. For example, if a patient fails to achieve remission and continues to experience proteinuria, renal biopsy finding sometimes change from MGAs to FSGS. Considering these phenomena, pathological findings in SRNS may simply result from persistent proteinuria.
Rituximab therapy for recurrence of nephrotic syndrome after kidney transplantation
Patients with SRNS who progress to ESRD are at high risk of recurrence of nephrotic syndrome after kidney transplantation. Approximately 30% of these patients develop recurrence after the first allograft. Young age (< 15 years) at onset of nephrotic syndrome, rapid progression to ESRD (< 3 years), late steroid-resistance, MGA (rather than FSGS), live donor allograft, and non-genetic forms of nephrotic syndrome were reported as risk factors for recurrence [40,41,42]. Patients with relapsed nephrotic syndrome after kidney transplantation are at increased risk of allograft failure. Moreover, after the loss of the allograft, the risk of recurrence of nephrotic syndrome following subsequent kidney transplantation was reported at 80–100% [43]. Traditionally, plasma exchange and high-dose cyclosporine were administered for the treatment of this disease.
Nozu et al. reported a case of a 12-year-old boy who suffered from recurrence of nephrotic syndrome and posttransplant lymphoproliferative disorder (PTLD). The patient was treated with rituximab (four doses, once weekly) resulting in the improvement of proteinuria and PTLD [44]. This case study was the first description of rituximab treatment in a patient with recurrence of nephrotic syndrome after kidney transplantation. Subsequently, several case series describing rituximab treatment for this condition were reported [32, 45, 46]. Combined therapy with plasma exchange and rituximab resulted in complete or partial remission in 60% of patients enrolled in the IPNA multicenter study [45] and 64.1% according to a meta-analysis of 18 reports comprising 39 patients in total [46]. However, it is difficult to evaluate the efficacy of rituximab treatment per se in patients with recurrence of nephrotic syndrome following kidney transplantation because other treatments, such as plasma exchange, were also administered to most patients.
Adverse events due to rituximab therapy
The most well-known adverse events (AEs) resulting from rituximab therapy are infusion reactions (IRs) and are typically observed within 24 h of treatment. The mechanism underlying IRs to rituximab is not fully understood, although the release of cytokines or chemokines due to B cell apoptosis is the most likely cause. Although IRs were reported in about 80% of non-Hodgkin lymphoma patients treated with rituximab, the frequency of IRs was lower (165 of 309 infusions, 53.4%) and their severity was milder in patients with nephrotic syndrome in our center [47]. Sixty-eight percent of AEs following rituximab therapy were classified as grade 1 and the remainder were classified as grade 2. Only 18% of AEs required medical intervention and no severe AEs were observed. Respiratory symptoms were the most common AE (66% of all events), 95% of which were observed within 3 h of initiation of rituximab infusion. B cell counts in patients with IRs were significantly higher than in patients without IRs. Patients who experienced IRs during their first rituximab treatment were more likely to experience recurrent IRs with subsequent treatments (odds ratio 3.64; p < 0.001).
Late-onset AEs to rituximab therapy can be problematic in some patients. Agranulocytosis has been reported as a late-onset complication of rituximab therapy. In our center, agranulocytosis occurred in 9.6% of all patients and was associated with 5.2% of all rituximab infusions [48]. The median time of onset of agranulocytosis was 66 days (range: 54–161 days) following rituximab therapy. Most patients experienced acute infections and received antibiotics. The median age of patients who developed agranulocytosis following rituximab therapy was 6.4 years at the time of treatment, and significantly younger than the median age of patients who did not develop agranulocytosis (median 12.5 years; p = 0.0009). It is important for patients to recognize this complication and to visit an emergency clinic as soon as possible upon developing fever.
Fatal pulmonary fibrosis in patients with refractory SRNS and pleural effusion after rituximab therapy has been reported [22]. Patients with cardiovascular or respiratory complications are categorized as at high risk of severe AEs after rituximab infusion. We recommend that patients be examined by routine chest radiograph and electrocardiography prior to rituximab therapy. The indication for rituximab treatment should be thoroughly discussed if patients with refractory SRNS are suffering from severe pleural effusion or their general condition has deteriorated due to severe edema [49].
Pneumocystis pneumonia [50], immune-mediated ulcerative colitis [51], and fulminant myocarditis [52] have been reported during rituximab-mediated B cell depletion in patients with nephrotic syndrome. Patients with persistent hypogammaglobulinemia have also been reported [53]. Progressive multifocal leukoencephalopathy due to JC virus [54] and reactivation of hepatitis B virus [55] were also reported following rituximab treatment, although not in patients with nephrotic syndrome. It is important that the possibility of rare but severe AEs following rituximab therapy be explained to patients and their caregivers. Decreased efficiency of vaccination during rituximab-mediated B cell depletion can also be a problem for children.
Future perspectives
In two recent large studies, 20–30% of pediatric SRNS cases were classified as genetic nephrotic syndrome [56, 57]. More than 50 disease-associated genes have been described, and more might be identified in the near future. In patients with genetic SRNS, the response rate to immunosuppressive agents is lower than in patients with non-genetic SRNS [56]. Buscher et al. reported a remission rate of 19% in patients with congenital SRNS compared with 78% in patients with non-genetic SRNS [58]. Thus, because genetic markers are useful for predicting responses to immunosuppressive agents, genetic analysis of patients with refractory SRNS should be conducted prior to administration of rituximab. If a patient is positive for a disease-associated gene, immunosuppressive treatments should be discontinued. Moreover, in patients with certain disease-associated genes (CDK20, DLC1, EMP2, ITSN1, ITSN2, KANK2, MAGI2, PLCE1, and TNS2), steroid and immunosuppressive agents have been reported to be effective [59,60,61,62,63]. The efficacy of rituximab therapy in patients with these mutations requires further evaluation.
To date, most reports of rituximab therapy for patients with refractory SRNS have been retrospective observational studies, excepting one RCT [39]. Thus, one must be aware of publication bias when considering these data. Rituximab treatment protocols, concomitant and subsequent treatments, and observation period differed among these studies. It remains possible that patients with genetic nephrotic syndrome were not completely excluded from these studies, as the number of known responsible genes for genetic nephrotic syndrome is increasing. All of these factors make evaluating the precise efficacy of rituximab treatment in patients with refractory SRNS from previous reports extremely challenging.
However, synthesizing the results of previous reports, the efficacy of rituximab treatment per se for patients with refractory SRNS appears to be limited. Patients with refractory SRNS, including patients who do not respond to CsA and MPT, should be treated not only with rituximab but also with concomitant treatments during B cell depletion, such as MPT, oral daily prednisolone therapy, and immunosuppressive agents. Further studies are needed to evaluate the efficacy and safety of rituximab for children with refractory SRNS. A large-scale, multicenter prospective study including a long-term observational period is needed to clarify these issues.
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KK has received lecture fees from Chugai Pharmaceutical Co., Ltd. and AbbVie GK. KIs has received lecture fees from Asahi Kasei Pharma, Chugai Pharmaceutical Co., Ltd., Zenyaku Kogyo Co., Ltd., and Novartis Pharma K.K. and grants from Asahi Kasei Pharma, Chugai Pharmaceutical Co., Ltd., and NovartisPharma K.K. MS has received a consulting fee from Zenyaku Kogyo Co. Ltd. SI has received grants from AbbVie GK., Asahi kasei Pharma Corporation, Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., CSL Behring, Eisai Co. Ltd., Maruho Co. Ltd., Japan Blood Product Organization, Kyowa Hakko Kirin Co., Ltd., Phizer Co. Ltd. and Teijin Pharma Ltd. SI has received lecture fees and/or consultant fees from AbbVie LLC, Astellas Pharma Inc., Alexion Pharma LLC, Chugai Pharmaceutical Co., Ltd., Eisai Co. Ltd., Daiichi Sankyo, Co., Ltd., Novartis Pharma K.K., Japan Blood Product Organization, JCR Pharmaceuticals Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Sanofi Genzyme Co. Ltd., Tanabe Mitsubishi Pharma, Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Co., Ltd. and Zenyaku Kogyo Co. Ltd.. KN has received lecture fees from Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K. and Otsuka Pharmaceutical Co., Ltd. KIi has received grants from Novartis Pharma K.K., Japan Blood Product Organization, AbbVie LLC, JCR Pharmaceuticals Co., Ltd., Daiichi Sankyo, Co., Ltd., Teijin Pharma Ltd., CSL Behring, Novo Nordisk Pharma Ltd., Air Water Medical Inc., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Eisai Co. Ltd.,Biofermin Pharmaceutical Co., Ltd., and Zenyaku Kogyo Co. Ltd., and lecture fees and/or consulting fees from Zenyaku Kogyo Co., Ltd., Novartis Pharma K.K., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Springer Japan K.K., Meiji Seika Pharma Co., Ltd., Asahi kasei Pharma Corporation, Medical Review Co.,Ltd., Nippon Boehringer Ingelheim Co., Ltd., Baxter Limited, Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co.,Ltd., Sanofi K.K., Alexion Pharma LLC., and Kyowa Hakko Kirin Co., Ltd.
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Kamei, K., Ishikura, K., Sako, M. et al. Rituximab therapy for refractory steroid-resistant nephrotic syndrome in children. Pediatr Nephrol 35, 17–24 (2020). https://doi.org/10.1007/s00467-018-4166-1
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DOI: https://doi.org/10.1007/s00467-018-4166-1